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Valproic acid
Valproic acid (VPA; pronunciation: vælˈproʊɪk 'æs ɪd; respelling pronunciation: val-proh-ik as-id) is an anticonvulsant primarily used to treat epilepsy and other seizure disorders, bipolar disorder, nerve pain and to prevent migraines. It was first synthesized in 1882 as a chemical analogue of valeric acid (which is found within valerian), and was initially thought to be an organic solvent with no pharmacologic effects, that is, it did not have any drug-type effect on living things, like animals or plants. Its anticonvulsant effects were later discovered, by accident in the early 1960s, in studies on rats; in these tests it was used as an organic solvent (for test anticonvulsant compounds) that was believed to be absent of pharmacologic activity. Then when they noticed every treatment group in these studies, including the vehicle group (where the animals were injected with solvent used to dissolve the supposedly active compounds), were protected from seizures. Medical uses Valproic acid is primarily used in the management of bipolar disorder, epilepsy and to prevent migraines. Recent research has shown that the combination of valproic acid with tretinoin might be useful in the management of non- acute myeloid leukaemia in patients intolerance of intensive chemotherapy regimens. Contraindications Contraindications for valproic acid treatment include: * Previous hypersensitivity reactions to valproic acid * Liver disease or significant liver impairment * Urea cycle disorder * -related disorders * Pregnancy, or women of childbearing potential that are either trying to get pregnant, or likely to engage in unprotected sex. Cautions Cautions include: * Risk of liver damage, age of less than 2 years is believed to be associated with an increased risk of fatal liver failure. * Risk of hyperammonaemia,Elevated ammonia levels in the blood if this occurs it is advised to discontinue the drug, especially if the treated person complains of lethargy or experiences abnormal behaviour. * Risk of pancreatitis, which has lead to some fatalities. * Porphyria-type reactions possible, hence should be avoided in those with a family or personal history of porphyria, where possible and practical. * Multi-organ hypersensitivity reactions reported * May alter some aspects of liver function tests * May cause false-positive ketone urine tests '''(which are used to detect diabetes mellitus, usually) * Not recommended after '''acute head injury to prevent seizures, as it may increase the risk of death (like from the increased tendency to bleed sometimes seen in people treated with valproic acid) in these cases * May cause sedation, impair driving ability and impair performance with regards to other skilled tasks * Family history '''of severe liver disorders', increases risk of fatal liver disorders. * Inborn '''metabolic' or degenerative disorders (like Tay Sachs disease, for instance), physical brain disease (like, for example, brain tumours or Alzheimer's disease), or severe seizure disorders associated with mental retardation may be at particular risk of liver damage or even failure * Increased bleeding tendency, so dose adjustments and bleeding time monitoring are advised during surgery. * If the treated individual is at a higher risk of developing . Side effects Note: see frequency of side effects for '''explanatory notes' on the terms used (like very common, uncommon, rare and very rare).'' Common side effects include: * Nausea and/or vomiting * Increased appetite * Weight gain * Tremor (which is usually related to the dose) * Thinning/loss of scalp hair (usually temporary) * Sensation of tingling and/or pins/needles * Drowsiness * Dizziness * Memory problems * Incoordination * Symptomless elevation of liver enzymes * Hyperammonaemia, usually without any symptoms * Low platelet count (thrombocytopenia), leading to an increased tendency to bleed; dose-dependent risk * Menstrual changes * Polycystic ovaries * Excess testosterone production in females, which can cause facial or chest hair to grow. Less common, yet potentially serious side effects (with their respective frequency in brackets) include: syndrome of inappropriate secretion of antidiuretic hormone '(uncommon), 'myelosuppression (very rare), liver injury (which has an incidence of 1 in 20,000), pancreatitis (pancreas swelling, rare or very rare; fatal cases have been reported, however), low body temperature '''(rare/very rare), '''increased bone fracture risk (usually with long-term treatment; rare/very rare), hypersensitivity reactions (involving multiple organ systems; rare/very rare), pleural effusion (the build up of fluid in the lungs; rare/very rare) and a brain disorder (which can cause permanent brain damage or even death) caused by hyperammonaemia (also rare/very rare). Levocarnitine is believed to be beneficial in preventing or treating hyperammonaemia, liver injury and pancreatitis. It may also be of use in the treatment of valproic acid overdose, according to at least one study which found it improved survival rates significantly. Special populations Pregnancy If taken during pregnancy there is an increased risk of birth defects, including heart defects, limb defects, facial defects, skull defects, urinary tract defects, neural tube defects (like spina bifida), etc. There is also an increased risk of mental retardation, autism and other developmental disabilities '''or '''delay. Breastfeeding It is excreted in breast milk, although the and , say it is safe to use during breastfeeding. Although at least one case of a potentially life-threatening reaction in an infant due to the presence of valproic acid has been reported. Kidney impairment Dosage adjustment may be required based based on free serum valproate levels. Add Liver impairment Avoidance is recommended, or close monitoring of liver function tests is advised, depending on the severity of the liver impairment. Children and adolescents At age less ''than 10 years, '''safety' has not been established. Mechanism of action It is believed to work via a variety of mechanisms, in epilepsy these mechanisms include: * Sodium channel inhibition * Succinic semialdehyde dehydrogenase inhibition, leading to elevated brain levels of succinic semialdehyde which in turn inhibits GABA transaminase, leading to elevated GABA levels * Calcium channel inhibition Whereas in bipolar disorder it likely acts by: * Histone deacetylase inhibition (likely also responsible for its anti-leukaemic effects) * Glycogen synthase kinase 3β inhibition External links * DailyMed; Depakene (solution/liquid-filled capsules) package insert, Stavzor (delayed release capsules) package insert and Valproic acid capsule package insert. * Medscape Reference patient handout. (Requires a free login) Notes Reference list Category:Anticonvulsants Category:Bipolar disorder Category:Differentiation therapies for cancer Category:Epilepsy Category:Histone deacetylase inhibitors